Evidence from a meta-analysis and systematic review reveals the global prevalence of mild cognitive impairment

Objective Mild cognitive impairment (MCI) is a preclinical and transitional stage between healthy ageing and dementia. The purpose of our study was to investigate the recent pooled global prevalence of MCI. Methods This meta-analysis was in line with the recommendations of Cochrane’s Handbook and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020. We conducted a comprehensive search using the PubMed, Embase, Web of Science, CNKI, WFD, VIP, and CBM from their inception to March 1, 2023. Quality assessment was guided by the Agency for Healthcare Research and Quality (AHRQ) methodology checklist. The pooled global prevalence of MCI was synthesized using meta-analysis via random effect model. Subgroup analyses were performed to examine considered factors potentially associated with MCI prevalence. Results We identified 233 studies involving 676,974 individuals aged above 50 years. All the studies rated as moderated-to-high quality. The overall prevalence of MCI was 19.7% [95% confidence interval (95% CI): 18.3–21.1%]. Subgroup analyses revealed that the global prevalence of MCI increased over time, with a significant rise [32.1% (95% CI: 22.6–41.6%)] after 2019. Additionally, MCI prevalence in hospitals [34.0% (95% CI: 22.2–45.7%)] was higher than in nursing homes [22.6% (95% CI: 15.5–29.8%)] and communities [17.9% (95% CI: 16.6–19.2%)], particularly after the epidemic of coronavirus disease 2019 (COVID-19). Conclusion The global prevalence of MCI was 19.7% and mainly correlated with beginning year of survey and sample source. The MCI prevalence increased largely in hospitals after 2019 may be related to the outbreak of COVID-19. Further attention to MCI is necessary in the future to inform allocation of health resources for at-risk populations.


Introduction
Mild cognitive impairment (MCI) is a condition characterized by mild cognitive deficit, while still retains the ability to perform daily living activities (Petersen et al., 2014).A recent review reported that up to 15.56% of community dwellers aged over 50 years were affected by MCI worldwide (Bai et al., 2022).MCI is considered as a symptomatic precursor of dementia, serving as an intermediate stage between normal aging and dementia.Over 46% of individuals with MCI progressed to clinical dementia within 3 years, which is one of the major causes of disability and dependency among older people (Trambaiolli et al., 2021).Therefore, MCI as predementia imposes potential economic burden on individuals, families, and society (Wang et al., 2022).
MCI is currently viewed as an "intervention window" for delaying the onset of dementia (Anderson, 2019;Liang et al., 2019;Wang et al., 2020).Understanding the global prevalence of MCI is essential for developing relevant strategies to prevent dementia.In recent years, several epidemiological studies have been conducted on MCI prevalence at different levels.For instance, Bai et al. revealed that the prevalence of MCI among community dwellers worldwide was over 15% and influenced by factors such as age, sex, educational level, and sample source (Bai et al., 2022).Deng et al. reported a prevalence rate of MCI in China was 15.4%, which was associated with unhealthy lifestyles such as alcohol consumption and lack of exercise, as well as health conditions like diabetes, hypertension, coronary heart disease, and depression (Deng et al., 2021).This information is crucial for developing prevention strategies aimed at addressing these risk factors.However, there are significant heterogeneities among previous studies.First, some studies may reveal the partial results when investigating the prevalence of MCI among the global population.On the one hand, differences in population characteristics could lead to variation in prevalence.Specifically, populations with the high-risk diseases, such as diabetes and depression, have a higher MCI prevalence (Hasche et al., 2010;Bo et al., 2015), which could affect the accuracy of total prevalence in healthy individuals.On the other hand, differences in geographical distribution could also affect the precision of global MCI prevalence when investigators omitted evidence from other geographical areas and sample source (Bai et al., 2022;Chen et al., 2023).Second, during the same period and in the same region, different studies have reported significant disparities in results.For instance, two studies from China in 2019 produced significantly different prevalence: one reported 9.67% (Ruan et al., 2020), while the other reported 27.8% (Lu et al., 2019).Similarly, two studies conducted 1 year apart reported nearly a threefold difference in MCI prevalence results in China: one reported 33.3% in 2015, while the other reported 10.42% in 2016 (McGrattan et al., 2021).These discrepancies may be attributed to variations in study design, such as search sources, screening tools, and diagnostic criteria for MCI.Lastly, the outbreak of the coronavirus disease 2019 (COVID-19) has significantly impacted society, affecting the lifestyle and health of everyone.There is evidence suggesting that some patients who have recovered from COVID-19 exhibit cognitive deficits (Liu et al., 2021;Crivelli et al., 2022).Consequently, the prevalence of neurological diseases, including MCI, may be even more severe as a result of COVID-19.However, whether COVID-19 has increased MCI prevalence remains unknown, highlighting the need for more updated research into the prevalence of MCI.Therefore, a comprehensive and updated meta-analysis on the global prevalence of MCI is urgently needed to identify the risk factors and provide a reference for researchers and clinicians.The purpose of this study is to investigate the recent global prevalence of MCI among the widest possible population.

Methods
This systematic review was conducted in accordance with the recommendations of Cochrane's Handbook (Cumpston et al., 2019) and the Systematic Reviews and Meta-Analyses (PRISMA) 2020 (Page et al., 2021) (Supplementary File S2).These analyses relied solely on previously published studies, so ethical approval or patient consent was not required.

Search strategies
The eligible studies were identified through a comprehensive literature search in PubMed, Embase, Web of Science, CNKI, WFD, VIP, and CBM databases from their inception to March 1, 2023.A search strategy was employed using Medical Subject Headings (MeSH) terms associated with keywords and Boolean operators on "cognitive dysfunction, " "mild cognitive impairment, " "mild cognitive disorder, " "prevalence, " "epidemiology, " and "epidemiological study" et al.In addition, manual retrieval was performed on the reference lists of relevant reviews and meta-analysis to search for additional studies on MCI prevalence.All database specific search queries could be found in Supplementary File S1.

Inclusion and exclusion criteria
Inclusion criteria were developed based on the PICOS principle, including participants (P), outcomes (O), and study design (S): 1. Participants: Studies were included when participants were diagnosed with MCI using recognized criteria, such as Petersen criteria (P-MCI) (Ronald, 2011) review articles, letters to the editor, and articles published only in abstract form.4. Full texts or data could not be obtained for our analyses.

Literature selection and data extraction
All citations were downloaded and managed using EndNote X9 software (Thompson ISI Research Soft, Clarivate Analytics, Philadelphia, United States).First, duplicate items were retrieved and removed.Then, based on inclusion and exclusion criteria, three investigators (WXS, YYZ, and HLX) independently reviewed the titles, abstracts, and full texts of publications to exclude irrelevant studies.All the eligible citations were cross-checked again to ensure accuracy.The relevant key data from the included studies were extracted into Microsoft Excel worksheets: (1) basic information: first author, publication year; (2) baseline characteristics: sample size, cases, age, proportion of males, beginning of survey, diagnostic criteria, region.The corresponding authors were consulted to obtain the essential information missing in the original studies.

Quality assessment
Three researchers (WXS, YYZ, and HLX) independently assessed the methodological quality of the included studies using the Agency for Healthcare Research and Quality (AHRQ) methodology checklist (Rostom et al., 2004).The checklist included 11 items: (I) Define the source of information; (II) List inclusion and exclusion criteria for exposed and unexposed subjects or provide a reference to previous publications that describe these criteria; (III) Indicate time period used for identifying patients; (IV) Indicate whether or not subjects were consecutive if not population-based; (V) Indicate if evaluators of subjective components of were masked to other aspects of the status of the participants; (VI) Describe any assessments undertaken for quality control purposes; (VII) Explain any patient exclusions from analysis; (VIII) Describe how confounding was assessed and/or controlled; (IX) If applicable, explain how missing data were handled in the analysis; (X) Summarize patient response rates and completeness of data collection; (XI) Clarify what follow-up, if any, was expected and the percentage of patients for which incomplete data or follow-up was obtained.The quality score for individual study ranges from 0 to 11, with 1 point for each item, and the study quality is separated into three levels: low (0-3), moderate (4-7), and high (8-11) (Hu et al., 2015).Any disagreements and uncertainty were resolved by discussion.

Literature selection
We initially obtained 143,006 studies, including 142,706 citations from databases and 300 additional studies from manual retrieval.Then, 33,931 studies were excluded for duplication, 108,457 articles were removed due to irrelevant titles and abstracts.Subsequently, 385 studies were excluded for various reasons: 66 were not available in full, 31 were non-observational studies (RCT, reviews, commentaries, systematic reviews, meta-analysis, conference abstracts, case reports), 159 had no available data, 83 had unclear diagnostic criteria, and 46 were reduplicated.Finally, 233 studies were included in this meta-analysis.The study selection process is shown in Figure 1.And all included studies in this systematic review and meta-analysis showed in Supplementary File S4.

Characteristics and quality of included studies
The 233 included studies were conducted between 1981 and 2021, enrolling 676,974 individuals aged from 50 to 107 years old.Most studies were cross-sectional studies (N = 207, 88.8%) and conducted in Asia (N = 171, 75.0%).The common diagnostic criteria for MCI was P-MCI (N = 150, 77.7%).Other detailed information on study characteristics is presented in Table 1.
Study quality assessment scores ranged from 4 to 11, with 76 studies (32.6%) rated as "high quality" and 157 studies (67.4%) rated as "moderate quality." All the 233 studies scored no less than 3, so no study was excluded.Further details of the quality assessment are shown in Supplementary File S3.

Discussion
Previous studies revealed partial results when investigating the prevalence of MCI with different degrees of limitation.In our study, we conducted an extensive literature search based on seven electronic databases and manual retrieval, ultimately identifying 233 studies with a total of 115,958 participants.Furthermore, we included more variables of interest into subgroup analyses, such as sample source, basic diseases, the beginning year of survey, and others.Considering the COVID-19 pandemic period, we attached importance to the MCI prevalence before and after 2019.To our knowledge, this is the most recent meta-analysis to provide a comprehensive overview of MCI prevalence without any limitations in age or region.
We concluded that the global total prevalence of MCI is 19.7% (95% CI: 18.3-21.1%)among 233 included studies.In addition, Subgroup analyses revealed that the sample source and beginning year of survey were considered factors potentially associated with MCI prevalence (p-value 2 < 0.05) (Table 3).
On the one hand, the prevalence of MCI patients in hospitals [34.0%(95% CI: 22.2-45.7%)]was higher than those in nursing homes [22.6% (95% CI: 15.5-29.8%)]and communities [17.9% (95% CI: 16.6-19.2%)].Several previous studies also draw the consistent conclusions.For example, ] have a higher MCI prevalence than nonclinical patients [14.61% (95% CI: 14.4-14.8%)](Xue et al., 2018).The higher MCI prevalence in hospitals may be attributed to professional diagnosis and treatment procedures.Meanwhile, patients in hospitals have more apparent clinical symptoms of MCI and receive more attention from clinicians, which greatly improves the detection rate of MCI.Similarly, the population in nursing homes [21.2% (95% CI: 18.7-23.6%)]have a higher MCI prevalence than community dwellers [5.56% (95% CI: 13.2-18.0%)](Bai et al., 2022;Chen et al., 2023).Compared to those living in nursing homes, people living in the communities have better material and emotional support from The number of amnestic MCI (aMCI) and no amnestic MCI (naMCI) were reported in these studies.their families, which might make a difference in reducing MCI prevalence.
On the other hand, we found that the total prevalence of MCI increased over time, especially after 2019.Notably, before 2019, there were no significant differences in MCI prevalence among three sample sources.However, the MCI prevalence after 2019 in hospitals [61.7% (95% CI: 27.8-95.7%)]was significantly higher than those in nursing homes [16.1% (95% CI: 14.3-17.9%)]and communities [25.3% (95% CI: 17.4-33.2%)](Table 2).Since the COVID-19 outbreak globally in 2019, hospital with the support of limited health resources and medical personnel with professional clinical knowledge has become the main refuge for COVID-19 patients (Kadri et al., 2020;Wadhera et al., 2020).There is cumulative evidence suggesting that COVID-19 impacts brain function and is associated with an elevated risk of neurodegenerative conditions, including cognitive dysfunction (Miners et al., 2020;Nath, 2020;Alquisiras-Burgos et al., 2021).Various post-COVID-19 symptoms indicate that coronaviruses, including SARS-CoV-2, could infect the central nervous system (CNS) through hematogenous pathways or neuronal retrograde neuro-invasion.This infiltration leads to subsequent microglial activation and enduring neuroinflammation, with dysregulated neuro-immunity serving as a foundational cause of nerve cell damage (Ellul et al., 2020;Troyer et al., 2020).Supporting the theory that COVID-19 can influence and exacerbate cognitive dysfunction, our data reveals a notable spike in the prevalence of MCI in hospitals post-2019.However, this rate may be conservative.The causes for this speculation are likely multifactorial, such as patients avoidance of emergency care due to fear of COVID-19 or the increased threshold for hospitalization of non-COVID-19 patients by clinicians due to the severity and urgency of COVID-19 (Blecker et al., 2021), which could masks the true prevalence.Therefore, more studies are needed in the future to investigate the potential link between COVID-19 and MCI.

Strengths and limitations
Based on previous research, this meta-analysis is the latest metaanalysis to provide a comprehensive overview of MCI prevalence without any age and regional limitations.This meta-analysis may aid policymakers, clinicians in making decisions and clinical directions, thus facilitating future studies and clinical applications.Our study, including the most extensive information currently available, is the first to analyze the association between COVID-19 and global MCI prevalence.However, there are also some limitations.First, the included data is unevenly distributed across regions.A large number of studies have been included from Asia, Europe, and North America, while relatively few have been included from Africa, Oceania, and South America.This unbalanced distribution of literature across regions may introduce bias in subgroups.Naturally, due to the vast amount of data included, our study unavoidably presents significant publication bias.Finally, the MCI prevalence in post-COVID-19 era still requires further investigation to provide more accurate evidence for the allocation of medical and health resources.Notably, we found a significant correlation between beginning year of survey and the global prevalence of MCI, with prevalence rates rising significantly after 2019.Furthermore, it is noteworthy that the prevalence of MCI in hospital settings outstripped those in nursing homes and community settings, especially after 2019.This trend may be in part attributable to the outbreak of COVID-19.The potential connection between COVID-19 and MCI warrants further investigation in future studies.Lastly, we posit that our review holds substantial value for policymakers and clinicians.The insights gleaned can guide healthrelated decision-making processes and inform the strategic allocation of health resources to better serve patients with MCI.
FIGURE 1The screening process of the literature.

TABLE 1
Characteristics of studies included in this meta-analysis.

TABLE 1 (
Continued)Funnel plot of pooled prevalence of MCI.

TABLE 2
The time trends in MCI prevalence from different sample sources.
p-value 1 is the p-value within subgroups; p-value 2 is the p-value across subgroups; 95%CI, 95% confidence interval.

TABLE 3
Subgroup analyses of MCI prevalence.
Our systematic review indicates that the current pooled global prevalence of Mild Cognitive Impairment (MCI) stands at 19.7%.
p-value 1 is the p-value within subgroups; p-value 2 is the p-value across subgroups; Region 1 is classified according to developed/developing countries; Region 2 is based on the region of each country.①95%CI, 95% confidence interval; ②P-MCI, classical Petersen's criteria of MCI; ③DSM, diagnostic and statistical manual of mental disorders; ④MCI, mild cognitive impairment.